Unsaturated 14, 15-cyclopropanoandrostanes, method for the production thereof and pharmaceutical preparations containing said compounds

ABSTRACT

Described are new, unsaturated 14,15-cyclopropano-androstanes of general formula (I) and their pharmaceutically acceptable salts, a process for their production and pharmaceutical preparations that contain these compounds. The compounds are characterized by hormonal (gestagenic and/or androgenic) activity and may be used for hormone replacement therapy.

This application is a 371 of PCT/DE99/01794 filed on Jun. 18, 1999.

DESCRIPTION

The invention relates to new, unsaturated14,15-cyclopropano-androstanes, their production and pharmaceuticalpreparations that contain these compounds.

Unsaturated 14,15-cyclopropano-androstanes of general formula I

are described.

In general formula I, R₁ is a hydrogen atom, a hydroxy group, analkyloxy, acyloxy, aryloxy, aralkyloxy or an alkylaryloxy group, aradical —OCONHR₉ or —OCOOR₉ with R₉ standing for a hydrogen atom, analkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in eachcase,

R₂ stands for a hydrogen atom, a hydroxyl group, an alkyl, acyl, aryl,aralkyl, alkylaryl group with 1-10 carbon atoms in each case,

for a radical —(CH₂)_(n)CH₂Y with n=0, 1 or 2, and Y stands for afluorine, chlorine, bromine or iodine atom, for a cyano, azido orrhodano group, for a radical —OR₁₀ or —SR₁₀ with R₁₀ standing for ahydrogen atom, an alkyl, aryl, aralkyl or alkylaryl radical with 1-10carbon atoms in each case or an acyl radical COR9 with R₉ standing foran alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms ineach case, a radical —OR₉ with R₉ standing for a hydrogen atom, analkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in eachcase,

for a radical —(CH₂)_(m)—CH═CH(CH₂)_(n)—R₈ with m=0, 1, 2 or 3 and n=0,1 or 2, and R₈ stands for a hydrogen atom, an alkyl, aryl, aralkyl oralkylaryl radical with 1-10 carbon atoms in each case or a hydroxylgroup, an alkoxy group or acyloxy group with 1-10 carbon atoms in eachcase,

a radical —(CH₂)_(o)C≡CR₁₁ with o=0, 1 or 2, and R₁₁ stands for ahydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl,aryl, aralkyl, alkylaryl or an acyl radical with 1-10 carbon atoms ineach case,

R₁ and R₂, independently of one another, stand for a keto, methylene, ordifluoromethylene group,

there can be a double bond between C-6 and C-7,

an α- or β-cyclopropane group X, indicated by X, that is shown standingfor a CZ₂ group with Z standing for a hydrogen, fluorine, chlorine,bromine or iodine atom, is located between C-14 and C-15,

R₃ and R₄, independently of one another, stand for a hydrogen atom, anα- or β-position alkyl group with 1-10 carbon atoms,

R₅ stands for an alkyl group with 1-3 carbon atoms.

The compounds according to the invention, the new, unsaturated14,15-cyclopropano-androstanes, have not yet been described. Theirbiological action is still unknown.

The object of this invention is to make available unsaturated14,15-cyclopropano-androstanes of general formula

and their pharmaceutically acceptable salts as well as a process fortheir production.

Another object is to make available pharmaceutical preparations thatcontain at least one compound of general formula I or theirpharmaceutically acceptable salts.

In general formula I

R₁ is a hydrogen atom, a hydroxy group, an alkyloxy, acyloxy, aryloxy,aralkyloxy or an alkylaryloxy group, a radical —OCONHR₉ or —OCOOR₉ withR₉ standing for a hydrogen atom, an alkyl, aryl, aralkyl or alkylarylradical with 1-10 carbon atoms in each case,

R₂ stands for a hydrogen atom, a hydroxyl group, an alkyl, acyl, aryl,aralkyl or alkylaryl group with 1-10 carbon atoms in each case,

R₂ stands for a radical —(CH₂)_(n)CH₂Y with n 0, 1 or 2, and Y standsfor a fluorine, chlorine, bromine or iodine atom, for a cyano, azido orrhodano group, for a radical —OR₁₀ or —SR₁₀ with R₁₀ standing for ahydrogen atom, an alkyl, aryl, aralkyl, or alkylaryl radical with 1-10carbon atoms in each case or an acyl radical COR₉, with R₉ standing foran alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms ineach case, a radical —OR₉ with R₉ standing for a hydrogen atom, analkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in eachcase,

for a radical —(CH₂)_(m)—CH═CH(CH₂)_(n —R) ₈ with m=0, 1, 2 or 3 andn=0, 1 or 2, and R₈ stands for a hydrogen atom, an alkyl, aryl, aralkylor alkylaryl radical with 1-10 carbon atoms in each case or a hydroxylgroup, an alkoxy group or acyloxy group with 1-10 carbon atoms in eachcase,

a radical —(CH₂)_(o)C≡CR₁₁ with o=0, 1 or 2, and R₁₁ stands for ahydrogen atom, a fluorine, chlorine, bromine or iodine atom, an alkyl,aryl, aralkyl, alkylaryl or an acyl radical with 1-10 carbon atoms ineach case,

R₁ and R₂, independently of one another, stand for a keto, methylene, ordifluoromethylene group,

there can be a double bond between C-6 and C-7,

an α- or β-cyclopropane group X, indicated by X, that is shown standingfor a CZ₂ group with Z standing for a hydrogen, fluorine, chlorine,bromine or iodine atom, is located between C-14 and C-15,

R₃ and R₄, independently of one another, stand for a hydrogen atom, anα- or β-position alkyl group with 1-10 carbon atoms,

R₅ stands for an alkyl group with 1-3 carbon atoms.

Most preferred are

17β-Hydroxy-14α,15α-methylen-androst-4-en-3-one (J 1193),

17α-hydroxy-14α,15α-methylen-androst-4-en-3-one,

17β-hydroxy-14β,15β-methylen-androst-4-en-3-one,

17α-hydroxy-14β,15β-methylen-androst-4-en-3-one,

17α-methyl,17β-hydroxy-14α,15α-methylen-androst-4-ene-3-one,

17β-methyl,17α-hydroxy-14α,15α-methylen-androst-4-en-3-one,

17α-methyl,17β-hydroxy-14β,15β-methylen-androst-4-en-3-one,

17β-methyl,17α-hydroxy-14β,15β-methylen-androst-4-en-3-one,

17β-hydroxy-6α-methyl-14α,15α-methylen-androst-4-en-3-one,

17α-hydroxy-6α-methyl-14α,15α-methylen-androst-4-en-3-one,

17β-hydroxy-6α-methyl-14β,15β-methylen-androst-4-en-3-one,

17α-hydroxy-6α-methyl-14β,15β-methylen-androst-4-en-3-one,

17β-hydroxy-7α-methyl-14α,15α-methylen-androst-4-en-3-one,

17α-hydroxy-7α-methyl-14α,15α-methylen-androst-4-en-3-one,

17β-hydroxy-7α-methyl-14β,15β-methylen-androst-4-en-3-one,

17α-hydroxy-7α-methyl-14β,15β-methylen-androst-4-en-3-one,

17β-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,

17α-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,

17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,

17α-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,

17α-methyl,17β-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,

17β-methyl,17α-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,

17α-methyl,17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,

17β-methyl,17α-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,

17β-hydroxy-7α,17α-dimethyl-14α,15α-methylen-androst-4-en-3-one,

17α-hydroxy-7α,17β-dimethyl-14α,15α-methylen-androst-4-en-3-one,

17β-hydroxy-7α,17α-dimethyl-14β,15β-methylen-androst-4-en-3-one,

17α-hydroxy-7α,17β-dimethyl-14β,15β-methylen-androst-4-en-3-one.

The invention also relates to a process for the production of thecompounds according to general formula I and their pharmaceuticallyacceptable salts, which is characterized in that a compound of generalformula II

in which R₁, R₂, R₃ and R₅ have the above-indicated meaning,

R₄ stands for a hydrogen atom, a hydroxy group, an alkoxyl group, anacyloxy group, an alkyl group with 1-10 carbon atoms in each case,

R₆ stands for a hydrogen atom, a hydroxy group, an alkoxyl group, anacyloxy group, an alkyl group with 1-10 carbon atoms in each case,

an α- or β-cyclopropane group X, indicated by X, that is shownrepresenting a CZ₂ group, in which Z can mean a hydrogen, fluorine,chlorine, bromine or iodine atom, is located between carbon atoms 14 and15,

cleaves the 3,5-cyclopropane grouping with acids, whereby mineral acids,organic acids and Lewis acids are preferred, and then converts into thedesired compounds of general formula I according to the methods that areknown to one skilled in the art.

Subjects of this invention are pharmaceutical substances for oral,rectal, subcutaneous, intravenous or intramuscular use, which togetherwith the commonly used vehicles and diluents can contain at least onecompound of general formula I or its acid addition salts as an activeingredient.

Pharmaceutical preparations of the invention are produced with thecommonly used solid or liquid vehicles and/or diluents and the generallycommonly used adjuvants corresponding to the desired type ofadministration in a suitable dosage and in a way that is known in theart. In the case of a preferred oral form for dispensing, preferablytablets, film tablets, coated tablets, capsules, pills, powders,solutions or suspension are also prepared as a depot form.

In addition, parenteral dosage forms such as injection solutions or elsesuppositories are also considered.

Dosage forms as tablets can be obtained by, for example, mixing theactive ingredient with known adjuvants, such as dextrose, sugar,sorbitol, mannitol, polyvinylpyrrolidone, explosives such as corn starchor alginic acid, binders such as starch or gelatin, lubricants such asmagnesium stearate or talc and/or agents that can achieve a depoteffect, such as carboxylpolymethylene, carboxymethylcellulose, celluloseacetate phthalate or polyvinyl acetate. The tablets can also consist ofseveral layers.

Coated tablets can be prepared analogously by coating cores that areproduced analogously to the tablets with agents that are commonly usedin tablet coatings, for example polyvinylpyrrolidone or shellac, gumarabic, talc, titanium dioxide or sugar. In this case, the coated tabletshell can also consist of several layers, whereby for example, theabove-mentioned adjuvants are used.

To improve the taste, the solutions or suspensions with the activeingredient according to the invention can be mixed with substances suchas saccharin, cyclamate or sugar and/or with flavoring substances, suchas vanillin or orange extract. In addition, they can be mixed withsuspension adjuvants, such as sodium carboxymethyl cellulose orpreservatives such as p-hydroxybenzoic acid.

The preparation of capsules can be carried out by mixing pharmaceuticalsubstance with vehicles such as lactose or sorbitol, which then areintroduced into the capsules.

The production of suppositories is preferably carried out by mixing theactive ingredient with suitable vehicles, such as neutral fats orpolyethylene glycols or derivatives thereof.

In addition, the pharmaceutical preparation forms can be percutaneouspreparation forms, e.g., transdermal therapeutic systems (TTS) or gels,sprays or ointments or intranasal preparation forms such as nose sprayor nose drops.

The unsaturated 14,15-cyclopropano-androstanes of general formula Iaccording to the invention are hormonal (gestagenic-and/orandrogenic-acting) compounds.

Thus, for example, the compound of general formula I, in which R₁represents a hydroxyl group; R₂, R₃, R₄ represent a hydrogen atom; R₅represents a methyl group; X represents a CH₂ group, and the14,15-cyclopropane ring is in α-position,17β-hydroxy-14α,15α-methylen-androst-4-en-3-one (J 1193), is anandrogen.

While the substance 17β-hydroxy-14α,15α-methylen-androst-4-en-3-one (J1193) with 24±3% binds to the androgen receptor of the rat prostate(reference substance: 17β-hydroxy-17α-methyl-estra-4,9,11-trien-3-one: R1881), there is virtually no binding to the progesterone receptor of therabbit uterus (reference substance: progesterone). In the HershbergerTest, a significant androgenic activity could be detected, however thereis very little gestagenic action in the pregnancy maintenance test. Thesubstance 17β-hydroxy-14α,15α-methylen-androst-4-en-3-one (J 1193) showsa pure androgenic profile of action that is almost free of gestagenicproperties.

In the compounds of general formula I according to the invention, thesetest results open up many possibilities for birth control in men,hormone replacement therapy in men and women or the treatment ofhormonally produced diseases in men and women, such as, for example,endometriosis, breast cancer or hypogonadism.

The compounds of general formula I according to the invention are to beexplained in more detail in the examples below, but are not limitedthereto.

EXAMPLE 1 17β-Hydroxy-14α,15α-methylen-androst-4-en-3-one

1 g of 17β-acetoxy-3,5-cyclo-6β-methoxy-14α,15α-methylen-androstane isdissolved in 50 ml of acetone, mixed with 0.1 ml of 60% perchloric acidand stirred for 40 minutes at 45° C. 20 ml of water is added, and thenit is neutralized with sodium bicarbonate. The solvent is drawn off, thecrystalline product is suctioned off and taken up in 200 ml of toluene.50 ml of this solution is distilled off, then 150 mg of aluminumisopropylate and 2 ml of cyclohexanone are added, and it is heated for40 minutes to 90° C. It is allowed to cool, acidified with 1Nhydrochloric acid and worked up in extract form. The organic extract isconcentrated by evaporation, and the residue is refluxed with 100 ml of1N methanolic potassium hydroxide solution for 60 minutes. Aftercooling, it is neutralized with 1N hydrochloric acid, and the solvent isdrawn off, whereby the product precipitates in solid form. Thecrystallizate is suctioned off and washed with water. The residue ischromatographed on silica gel (mobile solvent: toluene/ethyl acetate10:2) and recrystallized from ethyl acetate.

Flash point: 167-172° C.; H-NMR: 0.13 (1H, dd, J=5.6, 3.2 Hz,CH₂-bridge), 0.24 (1H, dd, J=8.3, 5.6 Hz, CH₂-bridge), 1.01 (3H, s,H-18), 1.26 (3H, s H-19), 3.49 (1H, dd, J=9.4, 6.6 Hz, H-17), 5.71 (1H,s, H-4).

EXAMPLE 2 17β-Hydroxy-14β,15β-methylen-androst-4-en-3-one

The substance is produced from17β-acetoxy-3,5-cyclo-6β-methoxy-14β,15β-methylen-androstane analogouslyto the instructions in Example 1.

Flash point 214-216° C.; H-NMR: 0.52 (1H, dd, J=8.3, 4.9 Hz,CH₂-bridge), 0.67 (1H, dd, J=4.9, 3.8 Hz, CH₂-bridge), 1.09 (3H, s,H-18), 1.20 (3H, s, H-19), 3.62 (1H, d, J=6.3 Hz, H-17), 5.71 (1H, s,H-4).

EXAMPLE 3 17β-Hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one

1 g of 17β-hydroxy-14β,15β-methylen-androst-4-en-3-one (production,Example 2) is refluxed with 1.2 g of chloranil in 50 ml of tert-butanolfor 30 minutes. It is allowed to cool and evaporated to the dry state.The residue is chromatographed on silica gel (mobile solvent:dichloromethane/ethyl acetate 10:1). For further purification, it isrecrystallized from ethyl acetate.

Flash point 180-190° C.; H-NMR; 0.8 (2H, m, CH₂-bridge), 1.12 (3H, s,H-18), 1.13 (3H, s, H-19), 3.65 (1H, d, J=6.2 Hz, H-17), 5.67 (1H, s,H-4), 5.95 (2H, m, H-1, H-2).

EXAMPLE 4 17β-Hydroxy-7α-methyl-14β,15β-methylen-androst-4-en-3-one

80 ml of THF is added to a solution of methylmagnesium iodide (preparedfrom 2.5 g of magnesium and 6.4 ml of methyl iodide in 80 ml of diethylether), it is cooled to −5° C., and 1 g of copper acetate-monohydrate,dissolved in 50 ml of THF, is added. It is cooled to −20° C., and then asolution of 5 g of 17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-onein 80 ml of THF is added in drops. After 2 hours, it is poured onto icewater/2N sulfuric acid and extracted with 3×80 ml of ethyl acetate. Theorganic extract is dried and concentrated by evaporation. The residue ischromatographed on silica gel (mobile solvent: dichloromethane/ethylacetate 10:1). For further purification, it is recrystallized from ethylacetate.

Flash point 140-145° C.; H-NMR: 0.59 (2H, m, CH₂-bridge), 1.02 (3H, d,J=8 Hz, H-7), 1.03 (3H, s, H-18), 1.12 (3H, s, H-19), 3.56 (1H, D, J=6Hz, H-17), 5.68 (1H, m, H-4).

What is claimed is:
 1. An unsaturated 14,15-cyclopropano-androstane offormula I

in which R₁ is a hydrogen atom, a hydroxy group, an alkyloxy, acyloxy,aryloxy, aralkyloxy or an alkylaryloxy group, a radical —OCONHR₉ or—OCOOR₉ with R₉ standing for a hydrogen atom, or an alkyl, aryl, aralkylor alkylaryl radical with 1-10 carbon atoms in each case, R₂ stands fora hydrogen atom, a hydroxy group, or an alkyl, acyl, aryl, aralkyl oralkylaryl group with 1-10 carbon atoms in each case, for a radical—(CH₂)_(n)CH₂Y wherein n=0, 1 or 2, and Y stands for a fluorine,chlorine, bromine or iodine atom, or for a cyano, azido or rhodanogroup, for a radical —OR₁₀ or —SR₁₀ with R₁₀ standing for a hydrogenatom, an alkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbonatoms in each case or an acyl radical COR₉, with R₉ standing for analkyl, aryl, aralkyl, or alkylaryl radical with 1-10 carbon atoms ineach case, for a radical —OR₉ with R₉ standing for a hydrogen atom, analkyl, aryl, aralkyl or alkylaryl radical with 1-10 carbon atoms in eachcase, for a radical —(CH₂)_(m)—CH═CH(CH₂)_(n)—R₈ wherein m=0, 1, 2 or 3and n=0, 1 or 2, and R₈ stands for a hydrogen atom, an alkyl, aryl,aralkyl or alkylaryl radical with 1-10 carbon atoms in each case, ahydroxyl group, or an alkoxy group or an acyloxy group with 1-10 carbonatoms in each case, or for a radical —(CH₂)_(o)C≡CR₁₁ wherein o=0, 1 or2, and R₁₁ stands for a hydrogen atom, a fluorine, chlorine, bromine oriodine atom, or an alkyl, aryl, aralkyl, alkylaryl or acyl radical with1-10 carbon atoms in each case, or R₁ and R₂, independently of oneanother, stand for a keto, methylene, or difluoromethylene group, meansthere can optionally be a double bond between C-6 and C-7, X stands fora CZ₂ group, with each Z standing independently for a hydrogen,fluorine, chlorine, bromine or iodine atom, and can be α- or β-X, R₃ andR₄, independently of one another, stand for a hydrogen atom, or an α- orβ-position alkyl group with 1-10 carbon atoms, and R₅ stands for analkyl group with 1-3 carbon atoms or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1, which is17β-Hydroxy-14α,15α-methylen-androst-4-en-3-one,17α-hydroxy-14α,15α-methylen-androst-4-en-3-one,17β-hydroxy-14β,15β-methylen-androst-4-en-3-one,17α-hydroxy-14β,15β-methylen-androst-4-en-3-one,17α-methyl,17β-hydroxy-14α,15α-methylen-androst-4-ene-3-one,17β-methyl,17α-hydroxy-14α,15α-methylen-androst-4-en-3-one,17α-methyl,17β-hydroxy-14β,15β-methylen-androst-4-en-3-one,17β-methyl,17α-hydroxy-14β,15β-methylen androst-4-en-3-one,17β-hydroxy-6α-methyl-14α,15α-methylen-androst-4-en-3-one,17α-hydroxy-6α-methyl-14α,15α-methylen-androst-4-en-3-one,17β-hydroxy-6α-methyl-14β,15β-methylen-androst-4-en-3-one,17α-hydroxy-6α-methyl-14β,15β-methylen-androst-4-en-3-one,17β-hydroxy-7α-methyl-14α,15α-methylen-androst-4-en-3-one,17α-hydroxy-7α-methyl-14α,15α-methylen-androst-4-en-3-one,17β-hydroxy-7α-methyl-14β,15β-methylen-androst-4-en-3-one,17α-hydroxy-7α-methyl-14β,15β-methylen-androst-4-en-3-one,17β-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,17α-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,17α-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,17α-methyl,17β-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,17β-methyl,17α-hydroxy-14α,15α-methylen-androsta-4,6-dien-3-one,17α-methyl,17β-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,17β-methyl,17α-hydroxy-14β,15β-methylen-androsta-4,6-dien-3-one,17β-hydroxy-7α,17α-dimethyl-14α,15α-methylen-androst-4-en-3-one,17α-hydroxy-7α,17β-dimethyl-14α,15α-methylen-androst-4-en-3-one,17β-hydroxy-7α,17α-dimethyl-14β,15β-methylen-androst-4-en-3-one, or17α-hydroxy-7α,17β-dimethyl-14β,15β-methylen-androst-4-en-3-one.
 3. Aprocess for the production of a compound according to claim 1comprising, in a compound of formula II,

in which R₁, R₂, R₃, X and R₅ have the meaning that is indicated inclaim 1, R₄ stands for a hydrogen atom, a hydroxy group, or an alkoxyl,acyloxy, or alkyl group with 1-10 carbon atoms in each case, and R₆stands for a hydrogen atom, a hydroxy group, or an alkoxyl, acyloxy, oralkyl group with 1-10 carbon atoms in each case, cleaving the3,5-cyclopropane group with an organic acid or a Lewis acid, andconverting the product into a compound of formula I.
 4. A pharmaceuticalcomposition that comprises at least one compound of formula (I)according to claim 1 and a pharmaceutically acceptable carrier.
 5. Amethod for birth control, hormone replacement therapy (HRT) or thetreatment of a hormonally produced disease, comprising administering acompound of formula (I) according to claim
 1. 6. A method of claim 5,wherein said disease is endometriosis, breast cancer or hypogonadism.